Inherited deficiencies of nucleoside and nucleotide metabolizing enzymes are associated with specific immunodeficiency diseases of children. Defects of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PHP) are the best described examples. The deoxynucleotide, dATP, is elevated 50 to 1000 fold above normal in erythrocytes, lymphocytes and bone marrow from an ADA deficient child. dGTP is elevated 10 fold above normal erythrocytes in PNP deficiency. Overproduction of deoxynucleotides appears to be the primary metabolic abnormality in patients with ADA and PNP deficiencies. Severe immunodeficiency disease is a consequence of the metabolic abnormality. Neither the pathways of abnormal synthesis of deoxynucleotides nor the reasons for selective deleterious effects on lymphoid precursors are known. We propose laboratory and clinical studies of deoxynucleotide metabolism in patients with inherited and acquired immunodeficiency diseases. We will measure deoxynucleotide pools, nucleoside kinases, interconverting enzymes, and DNA polymerases in peripheral blood cells, bone marrow, and thymocytes from affected patients and immunologically normal controls. We will systematically describe changes in nucleotide and nucleic acid metabolism of the immune system with age. Metabolism in lymphoid cells from patients will be compared to controls. Clinically, we have collected specimens of plasma, peripheral blood cells, and urine which are being analyzed to correlate clinical course of disease with types of therapy and quantity of abnormal metabolites. Immunodeficient mice and cell cultures from patients with ADA or PNP deficiency will complement studies in man.